Slobodan Obradovic

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients With Acute Myocardial Infarction Based on Individual Patient Data

RATIONALE The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. OBJECTIVE We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). METHODS AND RESULTS The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. CONCLUSIONS This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients’ mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann–Whitney estimator 0.54, 95% confidence interval [CI] 0.47–0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200–370 mL (60% of patients) (Mann–Whitney estimator 0.61, 95% CI 0.52–0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Autologous bone marrow-derived progenitor cell transplantation for myocardial regeneration after acute infarction.

BACKGROUND Experimental and first clinical studies suggest that the transplantation of bone marrow derived, or circulating blood progenitor cells, may beneficially affect postinfarction remodelling processes after acute myocardial infarction. AIM This pilot trial reports investigation of safety and feasibility of autologous bone marrow-derived progenitor cell therapy for faster regeneration of the myocardium after infarction. METHODS AND RESULTS Four male patients (age range 47-68 years) with the first extensive anterior, ST elevation, acute myocardial infarction (AMI), were treated by primary angioplasty. Bone marrow mononuclear cells were administered by intracoronary infusion 3-5 days after the infarction. Bone marrow was harvested by multiple aspirations from posterior cristae iliacae under general anesthesia, and under aseptic conditions. After that, cells were filtered through stainless steel mesh, centrifuged and resuspended in serum-free culture medium, and 3 hours later infused through the catheter into the infarct-related artery in 8 equal boluses of 20 ml. Myocardial viability in the infarcted area was confirmed by dobutamine stress echocardiography testing and single-photon emission computed tomography (SPECT) 10-14 days after infarction. One patient had early stent thrombosis immediately before cell transplantation, and was treated successfully with second angioplasty. Single average ECG revealed one positive finding at discharge, and 24-hour Holter ECG showed only isolated ventricular ectopic beats during the follow-up period. Early findings in two patients showed significant improvement of left ventricular systolic function 3 months after the infarction. There were no major cardiac events after the transplantation during further follow-up period (30-120 days after infarction). Control SPECT for the detection of ischemia showed significant improvement in myocardial perfusion in two patients 4 months after the infarction. Echocardiographic assessment in these two patients also showed significant improvement of systolic function three months after the infarction. CONCLUSION Preliminary results of the study showed that the transplantation of bone marrow-derived progenitor cells into the infarcted area was safe, and feasible, and might improve myocardial function. Further follow-up will show if this treatment is effective in preventing negative remodeling of the left ventricle and reveal potential late adverse events (arrhythmogenicity and propensity for restenosis).

Elevations in soluble CD40 ligand in patients with high platelet aggregability undergoing percutaneous coronary intervention.

High aggregatory responses despite antiplatelet treatment is associated with an increased risk of thrombotic complications following percutaneous coronary intervention (PCI). In the present study, we investigated the relationship between platelet aggregatory responses to ADP and the release of CD40L (sCD40L): an immunomodulatory compound involved in atherothrombosis – in patients undergoing PCI. ADP-induced platelet aggregation, sCD40L and soluble P-selectin (sP-selectin) were determined before and 24 h after PCI, in samples from 52 patients receiving aspirin and thienopyridines. Platelet aggregation to ADP above the median was defined as ‘high aggregation’, and aggregation below the median as ‘low aggregation’. Data below are medians and interquartile ranges. Patients with ‘high platelet aggregability’ had a significantly higher increase in both sCD40L (Δ-values: 0.78 (−0.19–3.18) vs. −0.65 (−2.10–0.00) ng/ml, P = 0.002) and sP-selectin (Δ-values: 8.0 (−2.00–16.00) vs. 4.50 (−13.00–0.50) ng/ml, P = 0.001) compared with patients with ‘low platelet aggregability’. In a multivariate linear regression analysis adjusted for clinical characteristics and type of preintervention therapy, the only independent predictors of sCD40L and sP-selectin were platelet aggregation to ADP before PCI (P < 0.001) and the combination of platelet aggregation to ADP before PCI and urgency of PCI (P < 0.001). Circulating CD40L is more markedly increased after PCI in patients with high ADP-induced platelet aggregation.

Clopidogrel cessation triggers aspirin rebound in patients with coronary stent

Premature discontinuation of clopidogrel in patients undergoing percutaneous coronary intervention is a significant risk factor for thrombotic adverse outcomes. However, recent studies indicate that even discontinuation of long‐term use of clopidogrel may be associated with multiple adverse outcomes, that is, rebound phenomenon whose mechanism is not definitely clear. The aim of the study was to examine the effect of clopidogrel withdrawal in those on combined aspirin and clopidogrel therapy.

Men with Lower HDL Cholesterol Levels have Significant Increment of Soluble CD40 Ligand and High-sensitivity CRP Levels Following the Cessation of Long-term Clopidogrel Therapy

AIM The aim of this study was to examine whether the termination of long-term clopidogrel therapy results in a proinflammatory state and whether lipid parameters influence the inflammatory response after stopping the drug. METHODS A prospective, multicenter study was conducted among 200 patients with implanted coronary stents who received dual antiplatelet therapy for one year, without ischemic or bleeding events. According to the guidelines, clopidogrel was discontinued after one year. In all patients, the high-sensitivity C-reactive protein (hsCRP), soluble CD40 ligand (sCD40L) and lipid [total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)] levels were measured twice: on the day of cessation of clopidogrel and 45 days after the termination of clopidogrel treatment. RESULTS In men (n=151), the sCD40L serum levels were significantly higher 45 days after the discontinuation of clopidogrel (p=0.007), while the hsCRP levels were not significantly different (p=0.407). Furthermore, when analyzed across the HDL-C quartiles, the hsCRP and sCD40L values were found to be associated with the levels of HDL-C after the discontinuation of clopidogrel in men. In addition, the men in the first HDL-C quartile exhibited the most pronounced increase in the sCD40L levels (p=0.001) and had significantly higher hsCRP levels (p=0.001) compared to the subjects in the other quartiles. Other lipid parameters did not show any associations with the sCD40L or hsCRP levels. CONCLUSIONS The discontinuation of clopidogrel is associated with higher increments in the sCD40L level, and a pronounced proinflammatory response is associated with a lower HDL-C concentration.

THERAPEUTIC APPROACH IN PATIENTS WITH A FLOATING THROMBUS IN THE RIGHT HEART

BACKGROUND The occurrence of a floating thrombus in the right heart, although rare, is a life-threatening condition requiring a specific approach. In most cases, these thrombi are a result of embolization from deep venous thrombosis, and have lodged temporarily in the right heart. The management of this condition is variable, depending on whether or not there is a thrombus entrapped within a foramen ovale (FO). OBJECTIVES To present the management of 2 patients with a free-floating thrombus in the right heart, and a third patient with an entrapped thrombus in the FO. CASE REPORTS Two patients with a free-floating thrombus in the right atrium who were treated with thrombolytic therapy had an immediate excellent outcome. The patient with a thrombus entrapped within the FO was scheduled for surgical removal of the thrombus due to an unacceptable risk of systemic embolization if treated with thrombolytic and anticoagulant therapy. Unfortunately, he developed an ischemic stroke on the fifth day of presentation, just a few hours before the scheduled surgery, despite meticulous monitoring of continuous heparin infusion with activated partial thromboplastin time. CONCLUSION Thrombolytic therapy is recommended in patients with a free-floating thrombus in the right heart. However, in patients with a thrombus entrapped within an FO, delaying surgical removal of the thrombus may be deleterious due to unpredictable systemic embolization.

PCI and clopidogrel: antiplatelet responsiveness and patient characteristics.

Objective This study on responsiveness to clopidogrel and aspirin evaluates its interaction with: (i) patient characteristics; (ii) procedure characteristics; (iii) antiplatelet dose. Methods and results After elective PCI, 60 patients receiving aspirin 100 mg daily, and clopidogrel 75mg daily were monitored with the PFA 100 test and VASP assay. Non-responsiveness to aspirin and clopidogrel was found in 23 (38%) and 18 (30%) of 60 patients, respectively. Seven (12%) patients were dual nonresponders. Non-responders to both aspirin and clopidogrel were more often smokers. Non-responders to clopidogrel, in addition had elevated infl ammatory markers (P < 0.05). Dual non-responders had (i) a higher platelet count, LDL, and CRP; (ii) a lower HDL (P < 0.05). Clopidogrel non-responders were receiving 150 mg clopidogrel, with a positive response in 72%. Eighty % of non-responders to 150 mg clopidogrel were also non-responders to aspirin. Conclusion Baseline patient characteristics and clopidogrel dose modify the antiplatelet response. Also, patients resistant to both aspirin and clopidogrel do no benefi t from an increased clopidogrel dose.

Women have right ventricular infarction more frequently than men.

Objective The objective of the study was to determine whether women signifi cantly have more frequently right ventricular infarction than men. Methods The study population consisted of consecutive patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous intervention. The following criteria were used for the diagnosis of right ventricular infarction: ST-segment elevation in one of the right precordial leads V4R-V6R for equal or more than 1 mm together with ST-segment elevation in at least two contiguous inferior leads. The odds ratio for the diagnosis was calculated according to gender. Searching PubMed, nine more relevant studies that used the same criteria for the diagnosis of right ventricular infarction were identifi ed and a meta-analysis was conducted. Results In our group of 517 consecutive patients with STEMI, 32 (23.5%) of 136 women and 42 (11.0%) of 381 men had RVI (odds ratio (OR) = 2.48, 95% confi dence interval (CI): 1.49-4.13; P= 0.001). Two hundred and seventy-fi ve patients had inferior STEMI and among them 32 (42.7%) of 75 women and 42 (23.1%) of 182 men, had a right ventricular infarction (OR = 2.48, 95%CI: 1.40-4.40; P= 0.002). In a meta-analysis, a total number of 4,326 patients with inferior STEMI were included. Four hundred and thirty-seven (41.4%) out of 1,056 women and 1,221 (37.3%) out of 3,270 men, had been diagnosed with RVI (OR = 1.27, 95%CI: 1.09 - 1.48; P= 0.021). Conclusion Right ventricular infarctions occur more frequently in women than in men.

Myocardial damage size assessment in the zone of infarction for indicating rescue percutaneous coronary intervention

BACKGROUND The most important predictors of subsequent patients outcome after acute myocardial infarction (AIM) are infarct size, left ventricular ejection fraction, left ventricular volumes and presence and extent of residual myocardial ischemia. All of these variables can be directly determined through scintigraphic approaches. The presence and extent of myocardial ischemia are strong pre dictors for fatal and nonfatal cardiac events and improve risk statification beyound the information gleaned from clinical variables. CASE REPORT We presented a case of 66-years-old male with myocardial infarction of anteroseptal localization. Myocardial perfusion imaging (MPI) detected a large zone of residual ischemia (culprit lesion) within infarction zone. It has an important role in risk stratification after myocardial infarction, and indicates subsequent therapeutic decision making, in this case rescue percutaneous coronary intervention (PCI). After PCI we followed the therapy effect by MPI, and we found practically normal perfusion with minimal zone of defect perfusion in the apex. CONCLUSION Myocardial perfusion imaging has an important role in the initial evaluation and risk stratification of patients surviving myocardial infarction. It also plays a major role in guiding subsequent therapeutic decision making, and in monitoring the benefits of these therapeutic measures.